Diabetes mellitus includes a group of metabolic diseases having a cardinal symptom of chronic hyperglycemia based on insufficient insulin action. Glycemic control performed for the treatment is very significant as means for suppressing not only the onset of diabetes mellitus but also the onset and progression of complications such as retinopathy, nephropathy, neuropathy, cardiac infarction and brain infarction; and for improving the quality of life (QOL) and life expectancy of a patient. In Japan, 95% or more of diabetes mellitus patients are presumed to be type 2 diabetes mellitus (non-insulin dependent diabetes mellitus) patients. Recent years, a dipeptidyl peptidase-IV (DPPIV) inhibitor has been approved as a novel therapeutic agent for type 2 diabetes mellitus, and has attracted attention because it causes a small adverse reaction such as hypoglycaemia and can perform glycemic control with an excellent mechanism. The DPPIV converts incretin (gastric inhibitory polypeptide: GIP, glucagon-like peptide-1: GLP-1), which is a gastrointestinal hormone to stimulate insulin secretion by acting on pancreatic β cells, to its inactive type. Therefore, when the DPPIV is inhibited, the action of incretin can be retained to promote insulin secretion. The DPPIV is one of serine proteases, and is an enzyme that recognizes and cuts proline (Pro) or alanine (Ala) at the second site from the N-terminal of a peptide. It has been reported that the DPPIV acts strongly on peptides having proline and alanine at the second residue from the N-terminal, and further having lysine (Lys) and arginine (Arg) as the N-terminal residue (Non Patent Literature 1).
An inhibitory effect to increase of blood glucose level by protein hydrolysates has been reported. As the mechanisms of this action, an action to promote insulin secretion (Patent Literature 1), a glucose absorption inhibitory activity (Patent Literature 2), and promotion of glucagon-like peptide-1 (GLP-1) secretion (Patent Literature 3) have been reported. In some reports, inhibitory effect to increase of blood glucose level was recognized by an enzymatically decomposed product of layer (Patent Literature 4) and a peptide obtained by decomposing royal jelly (Patent Literature 5). There are some reports, in which no mechanisms were revealed. As a product obtained from milt of a fishery product as a starting material, protamine extracted from milt is known to have an amylase inhibitory activity (Non Patent Literature 2) and an action to promote GLP-1 secretion (Non Patent Literature 3).
Many compounds obtained by chemically synthesis have been reported by paying attention to the DPPIV inhibitory activity (Patent Literature 6), but such chemically synthesized products should be used carefully in consideration of a safety problem and an adverse reaction. As the DPPIV inhibitors derived from natural products, those are known such as peptides derived from a water-soluble fraction of cheese (Patent Literature 7), peptides derived from a milk protein (Patent Literature 8), enzymatically decomposed products of an azuki bean or a kidney bean (Patent Literature 9), peptides derived from gelatin (Patent Literature 10), and peptides derived from enzymatically decomposed products of gelatin extracted from a salmon skin (Non Patent Literature 4), etc.
Milt of a fishery product has a lower use value than eggs thereof, and has been not effectively used. Their uses are limited to a fertilizer or a feed. Even milt derived from salmon, which is comparatively well used, is used as a starting material of protamine or a nucleic acid, but the milt is disposed as industrial waste in an amount of 10,000 tons or more per year.